James P. Catania

Adoption of QbD tools and tactics by individual functional silos may result in isolated pockets of improved performance, and there is certainly an advantage to be gained by enhancing organizational competence in the fundamental tools of QbD. However, the full strategic potential of QbD may not be realized if there is an absence of coordinated leadership, and ironically, overall organizational performance may be degraded.

The broad cross-functional implications of effective integration of QbD into the overarching strategy of the enterprise and the downside potential of ineffective integration and functional coordination are the reasons leadership by executive management is essential.

For decades, the pharmaceutical and biotech industries have been mired in a flawed and costly regulatory and quality assurance paradigm. Raw-material specifications and process parameters were locked in at the clinical phase by a validation protocol, which documented that three batches of a product, produced under virtually identical conditions, had yielded in-specification results. As a result, quality assurance became almost exclusively dependent on ensuring a pedantic reproduction of validation conditions and on exhaustive raw material and final product release testing.

Ironically, this approach to quality has had collateral effects in other areas that have increased the risk of failure, inflated total lifecycle cost, and impeded improvement. For example, the R&D department has much more incentive to simply get past validation to produce product for the clinical phase than to optimize processes to minimize total life-cycle cost. Meanwhile, methodologies for designed experiments in product or process development that have been proven in other industries to significantly reduce total lifecycle cost and risk-of-failure have been viewed as incongruent with validation and, therefore, unnecessary.

Now, a new regulatory paradigm is emerging as FDA and international regulatory agencies are placing greater emphasis on fundamental understanding of manufacturing processes as the basis for a knowledge-driven, risk-management approach to quality. Increasingly, FDA's position is that pharmaceutical manufacturing should have reproducible manufacturing processes and, thereby, be able to mitigate the risk of an event that could threaten public safety. Instead of engaging in an adversarial relationship, the industry and FDA would share knowledge. Regulatory processes would be proportional to the level of risk and applied in a consistent and predictable manner. This collaboration represents a clear shift away from a long-standing position of rigid regulation and inspection to achieve quality standards.

These new approaches to regulation, compliance, and quality are embodied in the adopted quality guidelines of the International Conference on Harmonization.

ICH Q8 Pharmaceutical Development addresses the key concepts of QbD and design space (DS), and establishes the principle of designing quality into products and processes rather than testing for quality after the fact. ICH Q8 defines design space as the "multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality." The guidance goes on to say, "working within the design space is not considered as a change." This statement means that pharmaceutical manufacturers can adjust the process within the design space to make continuous improvements without formal regulatory approval. Companies have the opportunity to continuously reduce the costs and consequences of poor quality without fear of having to refile each time they change a product or process parameter.

ICH Q9 Quality Risk Management describes a systematic process for the assessment, control, communication, and review of quality risks. The guideline provides examples of quality risk-management tools. These principles and tools can be applied to all aspects of pharmaceutical quality including development, manufacturing, distribution, and the inspection and submission or review processes throughout the life cycle of drug substances, drug products, and biological and biotechnological products. From a business and operational point of view, the focus is no longer on rushing past validation but on fully understanding and managing risks from the product's inception and throughout its life cycle.

ICH Q10 Pharmaceutical Quality System outlines the goals of a quality system that can be applied to all phases of a product's life cycle. Where a company chooses to apply QbD and quality risk management linked to an appropriate pharmaceutical quality system, opportunities arise to enhance science- and risk management-based regulatory approaches.

As the industry continues to globalize, the need for international harmonization embodied in these initiatives will only grow more urgent. In the same manner, as QbD increasingly becomes a prominent component of new drug applications (NDAs), companies that have failed to adopt QbD will be at a distinct disadvantage.